Immune system activation (ISA) is a commonly recognized component of the heart failure syndrome. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-lbeta)- the blood borne products of ISA- activate the sympathetic nervous system. The overall hypothesis of this project is that these pro-inflammatory cytokines contribute to the augmented sympathetic drive in heart failure by their actions upon neurons in the paraventricular nucleus (PVN) of the hypothalamus. Two principal mechanisms for this proposed effect will be investigated. 1) Circulating cytokines induce catecholamine release in PVN. Increased catecholamine content in PVN has been associated with heightened sympathetic drive in other pathophysiologicalconditions, such as neurogenic hypertension, that are also characterized by increased activity of the renin-angiotensinsystem (RAS). The present studies will examine the hypothesis that catecholamine release in PVN, induced by circulating cytokines, activates sympatho-excitatory PVN neurons, and that this effect is facilitated by interactions in PVN between catecholamines and the RAS. 2) Cytokines induce the production of reactive oxygen species (ROS). Cytokines may be produced in the brain, and may enter the brain via a saturable membrane transport system. The present studies will examine the hypothesisthat in heart failure the presence of cytokines in the PVN induces ROS, which activates sympatho-excitatory PVN neurons. Finally, these studies will examine the mechanisms by which activation of PVN neurons by circulating or intrinsic cytokines might elicit an increase in sympathetic drive. Recent evidence suggests that signals descending from PVN require activation of an angiotensin type 1 receptor in rostral ventrolateral medulla (RVLM) to effect an increase in sympathetic drive. The present studies will determine whether sympatho-excitatoryPVN neurons activated by pro-inflammatory cytokines utilize this pathway. Electrophysiologicalrecordingtechniques will be used in conjunction with push-pull analysis of peptide/transmitter release and immunohistochemistry to test these hypotheses in rats with ischemia-induced heart failure and in sham-operated controls. These studies will provide important new insightsinto the role of the pro-inflammatorycytokines in heart failure.